Current status of chemotherapy for uterine sarcoma in Japan

To date, no standard treatment has been established for uterine leiomyosarcoma. The 2020 edition of the NCCN Guidelines states that follow-up or chemotherapy should be considered for stage I of uterine leiomyosarcoma. However, as treatment options after complete resection for leiomyosarcoma Ⅱ stage or stage Ⅲ, chemotherapy and/or radiation therapy has been proposed.

In the latter half of the 1980s, DOX/CDDP therapy (doxorubicin 60 mg/m2, and cisplatin 100 mg/m2) was covered by insurance as chemotherapy for malignant osteosarcoma in Japanese clinical practice. Even now, in Japan of clinical practice guidelines, DOX/CDDP therapy has been shown to be a standard combination therapy for malignant osteosarcoma.

To date, there have not been rigorous comparative clinical trials for uterine leiomyosarcoma in Japan. In Japan gynecological species Society sponsored, in 2020 from 2019, in sub-group test for uterine sarcoma that conducted by our clinical group, the response rate of chemotherapy that included doxorubicin against uterine leiomyosarcoma has been investigated.

In our clinical research the response rate of doxorubicin alone 80 mg / m2 is 10%, the response rate of the combination therapy of ifosfamide 7.5 g/m2 (3.75 g/m2/day x 2 days) and doxorubicin 60 mg/m2 (30 mg/m2/day x 2 days) was 14%, the response rate of the triple therapy of mitomycin 8 mg/m2, doxorubicin 40 mg/m2, and cisplatin 60 mg/m2 was 19%.

From this study, the response rate of triple therapy tended to be high for uterine leiomyosarcoma. However, at present, sufficient response rates have not been shown for monotherapy and combination therapy for uterine leiomyosarcoma.

In December 2018, the Japan Ministry of Health, Labor and Welfare announced that the clinical treatment of pembrolizumab was approved as treatment for solid tumors with high-frequency microsatellite instability (MSI-High) that worsened after cancer chemotherapy (only when standard treatment is difficult).

In clinical practice, the prevalence of MSI-H patients was examined using an insurance-listed MSI (microsatellite instability) test kit in solid cancer patients (25,789 samples) who will be treated with anticancer drugs. From large-scale data of clinical testing company, cancer of the MSI-H that exists widely revealed in a variety of cancer types.

Solid tumors identified as MSI-H, was 3.75% of the total solid tumors. Mesothelioma, sarcoma, prostate cancer, and ovarian germ cells were found in patients with MSI-H/MSI-I tumors with Lynch syndrome confirmed in a clinical study (25789 samples) conducted by the Japan Cancer Society. In MSI-H patients, the content of sarcomas, including uterine leiomyosarcoma, was 0.14% (37/25789).

Currently, our research group is planning a clinical trial on the response rate of combination therapy with immune checkpoint inhibition and doxorubicin for uterine leiomyosarcoma. In the near future, our research group will publish a protocol for clinical trials.

Ethics statement
This study was reviewed and approved by the Central Ethics Review Board of the National Hospital Organization of Japan (Meguro, Tokyo, Japan). The approved number for this study is 50-201504. In order to carry out this research, the authors attended a research ethics education course (e-APRIN) conducted by Association for the Promotion of Research Integrity (APRIN; Shinjuku, Tokyo, Japan). The approved numbers of e-APRIN are AP0000151756, AP0000151757, AP0000151758, AP0000151769.

Disclosure
The authors declare no potential conflicts of interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Acknowledgments
We thank Professor Susumu Tonegawa (Nobel Prize in Physiology and Medicine , Massachusetts Institute of Technology (MIT), Cambridge, MA) for his research assistance. This study was supported in part by grants from the Japan Ministry of Education, Culture, Science and Technology (No. 24592510, No. 15K1079, and No. 19K09840); Foundation of Osaka Cancer Research; Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care; Foundation for Promotion of Cancer Research; Kanzawa Medical Research Foundation; Shinshu Medical Foundation; and Takeda Foundation for Medical Science.

Doctor specializing in cancer medicine

JAMA Oncology Published on January 2021. by Kyoto@Takuma H